Bioerodible endoprosthesis

ABSTRACT

An endoprosthesis can include a body including an underlying portion and a surface portion overlying the underlying portion. The underlying portion can include a bioerodible metal in the form of a matrix and corrosion enhancing deposits within the matrix. The surface portion including the bioerodible metal of the matrix. The surface portion having a first erosion rate when exposed to a physiological environment and the underlying portion having a second erosion rate when exposed to a physiological environment that is greater than the first erosion rate.

TECHNICAL FIELD

This invention relates to bioerodible endoprostheses, and moreparticularly to bioerodible stents.

BACKGROUND

The body includes various passageways such as arteries, other bloodvessels, and other body lumens. These passageways sometimes becomeoccluded or weakened. For example, the passageways can be occluded by atumor, restricted by plaque, or weakened by an aneurysm. When thisoccurs, the passageway can be reopened or reinforced, or even replaced,with a medical endoprosthesis. An endoprosthesis is typically a tubularmember that is placed in a lumen in the body. Examples of endoprosthesesinclude stents, covered stents, stent-grafts, and vascular closure pins.

Endoprostheses can be delivered inside the body by a catheter thatsupports the endoprosthesis in a compacted or reduced-size form as theendoprosthesis is transported to a desired site. Upon reaching the site,the endoprosthesis is expanded, for example, so that it can contact thewalls of the lumen.

The expansion mechanism can include forcing the endoprosthesis to expandradially. For example, the expansion mechanism can include the cathetercarrying a balloon, which carries a balloon-expandable endoprosthesis.The balloon can be inflated to deform and to fix the expandedendoprosthesis at a predetermined position in contact with the lumenwall. The balloon can then be deflated, and the catheter withdrawn.

In another delivery technique, the endoprosthesis is formed of anelastic material that can be reversibly compacted and expanded, e.g.,elastically or through a material phase transition. During introductioninto the body, the endoprosthesis is restrained in a compactedcondition. Upon reaching the desired implantation site, the restraint isremoved, for example, by retracting a restraining device such as anouter sheath, enabling the endoprosthesis to self-expand by its owninternal elastic restoring force.

The endoprosthesis can carry a drug, such as an antiproliferative, toreduce the likelihood of restenosis, i.e., reclosure of the vessel dueto immune reactions by the body at the treatment site.

SUMMARY

An endoprosthesis is described that includes a body including anunderlying portion and a surface portion overlying the underlyingportion. The underlying portion including a bioerodible metal in theform of a matrix and corrosion enhancing deposits within the matrix. Thesurface portion including the bioerodible metal of the matrix. Thesurface portion having a first erosion rate when exposed to aphysiological environment and the underlying portion having a seconderosion rate when exposed to a physiological environment that is greaterthan the first erosion rate.

The corrosion enhancing deposits can include nano-bubbles of noble gases(e.g., helium, argon, neon, kripton or a combination thereof). Thenano-bubbles can have an average diameter of between 1 nm and 600 nm.The corrosion enhancing deposits, in some embodiments, can includesilver, manganese, or a combination thereof. In other embodiments, thecorrosion enhancing deposits can include the same elements as thebioerodible metal and increase the corrosion rate by increasing thesurface tension. In some embodiments, the corrosion enhancing depositscan be more or less noble then the bioerodible metal and form a galvaniccouple with the bioerodible metal when the corrosion enhancing depositsare exposed to a physiological environment. In some embodiments, thecorrosion enhancing deposits are more noble and act as an anode toaccelerate the corrosion rate of the bioerodible metal. In otherembodiments, the corrosion enhancing deposits are less noble and erodefaster than the bioerodible metal and leave an increased surface area ofthe matrix material which accelerates the corrosion rate of thebioerodible metal once the corrosion enhancing deposits erode away.

The surface portion can be substantially free of the corrosion enhancingdeposits. The surface portion can have a thickness of between 0.2micrometers and 3 micrometers. In some embodiments, the surface portioncan be composed essentially of the bioerodible metal. The surfaceportion can have a substantially smooth upper surface. The term“substantially smooth” as used herein requires an Ra of 0.5 μm or less.

The bioerodible metal can include iron or an alloy thereof. In otherembodiments, the bioerodible metal can include magnesium, zinc,tungsten, and alloys thereof.

The endoprosthesis can be a stent. In other embodiments, theendoprosthesis can be a vascular closure pin.

In another aspect, method of producing an endoprosthesis is described.The method includes implanting ions into a body including a bioerodiblemetal to create an underlying portion including corrosion enhancingdeposits within a matrix of the bioerodible metal and a surface portionoverlying the underlying portion comprising the bioerodible metal. Theunderlying portion has a greater erosion rate when exposed tophysiological environment than the surface portion of the bioerodiblemetal body.

The implanted ions can be noble ions that create the corrosion enhancingdeposits of nano-bubbles of noble gases in the matrix of the bioerodiblemetal and/or ions that react with the bioerodible metal to produce thecorrosion enhancing deposits. In some embodiments, the ions areimplanted using IBAD or PIII ion implanting processes. In someembodiments, the ions can be implanted at a dose of less than 1×10¹⁶ions/cm². The ions can be implanted using a minimum energy of at least10 keV (e.g., within the range of 10 keV and 100 keV). In someembodiments, the temperature range during the ion implanting process isbetween 100 C. and 500 C. In some embodiments, the temperature is 0.2times the melting temperature of the bioerodible metal (e.g., between100 C. and 150 C. for most magnesium based bioerodible alloys andbetween 200 C. and 350 C. for most iron based bioerodible alloys).

The surface portion can be substantially free of the corrosion enhancingdeposits. In some embodiments, the endoprosthesis can include additionalsurface layers deposited on the surface portion after the implantationof the corrosion enhancing deposits.

The bioerodible metal body can be a stent or a stent precursor. In otherembodiments, the bioerodible metal body can be a vascular closure pin orvascular closure pin precursor.

The details of one or more embodiments are set forth in the accompanyingdrawings and the description below. Other features, objects, andadvantages will be apparent from the description and drawings, and fromthe claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is a perspective view of an example of an expanded stent.

FIGS. 2A-2C depict cross sections of a stent strut having an implantedsubcutaneous layer of ions according to different embodiments.

FIG. 3 depicts a stent strut erosion profile.

FIG. 4 illustrates exemplary environments for implanting ions into astent.

Like reference symbols in the various drawings indicate like elements.

DETAILED DESCRIPTION

Referring to FIG. 1, a stent 20 can have the form of a tubular memberdefined by a plurality of struts. The struts can include a plurality ofbands 22 and a plurality of connectors 24 that extend between andconnect adjacent bands. During use, bands 22 can be expanded from aninitial, small diameter to a larger diameter to contact the stent 20against a wall of a vessel, thereby maintaining the patency of thevessel. Connectors 24 can provide stent 20 with flexibility andconformability that allow the stent to adapt to the contours of thevessel.

The stent includes a bioerodible metal. Examples of bioerodible metalsinclude iron, magnesium, tungsten, zinc, and alloys thereof. Forexample, the bioerodible metal can be a bioerodible iron alloy thatincludes up to twenty percent manganese, up to 10 percent silver, and upto five percent carbon. The bioerodible metal can also be a bioerodiblemagnesium alloy that includes up to nine percent aluminum, up to fivepercent rare earth metals, up to five percent zirconium, up to fivepercent lithium, up to five percent manganese, up to ten percent silver,up to five percent chromium, up to five percent silicon, up to fivepercent tin, up to six percent yttrium, and up to ten percent zinc.Suitable magnesium bioerodible alloys include ZK31, which includes threepercent zinc and one percent zirconium, ZK61, which includes six percentzinc and one percent zirconium, AZ31, which includes three percentaluminum and one percent zinc, AZ91, which includes nine percentaluminum and one percent zinc, WE43, which includes four percent yttriumand three percent rare earth metals, and WE54, which includes fivepercent yttrium and four percent rare earth metals. A stent including abioerodible metal can reopen and/or reinforce a body passageway, yetbreakdown overtime so that the stent is no longer present in the bodypassageway after a healing process is complete. Different bioerodiblemetals and stent strut structures can have different erosion rates whenexposed to a physiological environment. Accordingly, the stent can bedesigned based on the erosion characteristics of the stent struts tomaintain the desired structural properties for a desired period of time.

As shown in FIGS. 2A-2C, a stent strut (e.g., a band 22 and/or aconnector 24) includes a surface portion 32 and an underlying portion34. In some embodiments, as shown in FIG. 2A, the underlying portion 34can be along the perimeter of the stent strut. In other embodiments, asshown in FIGS. 2B and 2C, the underlying portion 34 can be along selectsides of the stent strut, e.g., along the inner diameter and/or outerdiameter of the stent. In some embodiments, as shown in FIG. 2C, thestent strut can have an underlying portion 34 along the outer diameterof the stent strut and an additional coating 38 along the innerdiameter.

The surface portion 32 overlies the underlying portion 34. The surfaceportion 32 includes a bioerodible metal and the underlying portion 34includes corrosion enhancing deposits 28 within a matrix of thebioerodible metal. Upon implantation within a physiological environment,the surface portion 32 erodes at a first rate. Once the surface portionhas eroded to expose to the underlying portion to the physiologicalenvironment, the underlying portion 34 erodes at a second rate that isfaster than the first rate. An example of such an erosion profile isdepicted in FIG. 3. As shown, the thickness of the strut decreases overtime. During an initial erosion period 42, the surface portion 32 erodesat the first rate. During this initial erosion period 42, thebioerodible stent provides a mechanical support function. Once thesurface portion 32 has eroded away to expose the underlying portion 34to the physiological environment, an accelerated erosion period 44 canbe due to the presence of the corrosion enhancing deposits 28 within amatrix of the bioerodible metal. By having a stent with a first erosionrate that is slower than a second erosion rate, the stent strut can bedesigned to have smaller initial dimensions than a stent having aconstant erosion rate because the first erosion rate preserves thestructural properties of the stent during an initial healing processduring the initial erosion period 42. The accelerated erosion period 44then reduces the amount of time that a weakened stent strut remainspresent within a body passageway.

The surface portion 32 can have a thickness of between 0.1 micrometersand 3 micrometers. The surface portion 32 can include a substantiallysmooth upper surface. The term “substantially smooth” as used hereinrequires an R_(a) of 0.5 μm or less. The surface portion 32 can includethe same bioerodible metal included in the underlying portion. Thesurface portion 32 can be essentially free of any corrosion enhancingdeposit 28. In some embodiments, the surface portion 32 can beessentially free of other constituents other than the bioerodible metal.In some embodiments, stent 20 can include additional surface layerswhich can be deposited after the deposition of the corrosion enhancingdeposits. For example, the additional surface layers can be formed bythe deposition of the bioerodible metal on the surface portion 32 byvapor deposition or pulsed laser deposition techniques. These additionalsurface layers can have a thickness of 10 micrometers or greater.

The underlying portion 34 includes the corrosion enhancing deposits 28.In some embodiments, the underlying portion can have a thickness of atleast 1 micrometer. In some embodiments, the thickness can be between 2micrometers and 3 micrometers. The corrosion enhancing deposits 28 canbe positioned within the underlying portion by implanting ions usingenergies that implant the ions within the underlying portion whileleaving the surface portion substantially free of the corrosionenhancing deposits 28. The energy level of the ions at the time ofimplantation determines the depth of implantation. For example, thecorrosion enhancing deposits 28 can be produced by implanting ions witha minimum energy of 10 keV. In some embodiments, the ions can beimplanted within an energy range of between 10 keV and 100 keV. Thethicknesses of the surface portion 32 and the underlying portion 34 canbe determined by the energy range used to implant the ions. Thethickness and depth of the underlying portion are also partiallydetermined by the diffusion of embedded ions within the bioerodiblemetal. The embedded ions can create a pressure gradient normal to thesurface which can force the ions further into the stent strut. Thispressure gradient can force ions further into the bioerodible material.The implanting of ions to form the corrosion enhancing deposits canincrease the erosion rate of the underlying portion 34 by creating highstress areas and/or compression regions surrounding each corrosionenhancing deposit 28. In some embodiments, the ions can be implantedusing Ion Beam Assisted Deposition (“IBAD”) or Plasma Immersion IonImplantation (“PIII”). In some embodiments, the temperature range duringthe ion implanting process is between 100 C. and 500 C. In someembodiments, the temperature is about 0.2 times the melting temperatureof the bioerodible metal (e.g., between 100 C. and 150 C. for mostmagnesium based bioerodible alloys and between 200 C. and 350 C. formost iron based bioerodible alloys).

FIG. 4 illustrates an exemplary environment for performing PIII. Inorder to perform PIII, a precursor of stent 20 is inserted into achamber 50. The precursor of stent 20 includes a bioerodible metal(e.g., commercially pure iron). Chamber 50 is a vacuum chamber createdby a vacuum 54 containing a plasma 56. Plasma 56 contains ions to beimplanted into stent 20 to form the corrosion enhancing deposits 28. Theprecursor of stent 20 is pulsed repeatedly with negative voltages frompulser 58. As a result of the pulses of negative voltages, electrons arerepelled away from stent 20 and positive ions 60 are attracted to thenegatively charged stent 20. As a result, positive ions will strike allthe surfaces of stent 20 and be embedded in and/or deposited onto stent20.

The corrosion enhancing deposits 28 can include nano-bubbles of noblegases. Nano-bubbles of noble gases can increase the erosion rate of thebioerodible metal by increasing the surface area of the bioerodiblemetal. Nano-bubbles of noble gases can be formed in the matrix of thebioerodible metal by implanting noble ions. For example, the corrosionenhancing deposits 28 can include nano-bubbles of helium, argon, neon,and/or kripton gas. The nano-bubbles can have an average diameter ofbetween 1 nm and 600 nm. When implanting noble ions to producenano-bubbles of noble gases within the underlying portion 34, the dosecan be controlled to prevent the migration of the nano-bubbles to thesurface portion 32. In some embodiments, the dose of noble ions ismaintained at less than 1×10¹⁶ ions/cm².

The corrosion enhancing deposits 28 can include solid materials whichaccelerate the erosion process. For example, ions can be implanted thatreact with or alloy with the bioerodible metal to form corrosionenhancing deposits 28. For example, the corrosion enhancing deposits caninclude silver, copper, and/or manganese. In other embodiments, thecorrosion enhancing deposits can include the same elements as thebioerodible metal and increase the corrosion rate by increasing thesurface tension. In some embodiments, the resulting corrosion enhancingdeposits 28 can increase the erosion rate of the underlying portion 34by separating from the remaining matrix once exposed to thephysiological environment. In some embodiments, the corrosion enhancingdeposits can be more or less noble then the bioerodible metal and form agalvanic couple with the bioerodible metal when the corrosion enhancingdeposits are exposed to a physiological environment. In someembodiments, the corrosion enhancing deposits are more noble and act asan anode to accelerate the corrosion rate of the bioerodible metal. Inother embodiments, the corrosion enhancing deposits are less noble anderode faster than the bioerodible metal and leave an increased surfacearea of the matrix material which accelerates the corrosion rate of thebioerodible metal once the corrosion enhancing deposits erode away. Forexample, silver and copper would form a galvanic couple that wouldaccelerate the corrosion of iron.

The corrosion enhancing deposits 28, in some embodiments, may notpenetrate into a central portion 36 of the stent strut. As shown in FIG.3, once the underlying portion containing the corrosion enhancingdeposits 28 has eroded, the remainder of the stent strut can continue toerode during a bulk erosion period 46. The erosion rate during the bulkerosion period 46 can be slower than the erosion during the acceleratederosion period 44, but faster than the initial erosion period 42, due toan increase in the surface area of the stent strut due to variations inthe erosion of the stent.

Stent 20 can be of any desired shape and size (e.g., superficial femoralartery stents, coronary stents, aortic stents, peripheral vascularstents, gastrointestinal stents, urology stents, and neurology stents).Depending on the application, the stent can have a diameter of between,for example, 1 mm to 46 mm. In certain embodiments, a coronary stent canhave an expanded diameter of from 2 mm to 6 mm. In some embodiments, aperipheral stent can have an expanded diameter of from 5 mm to 24 mm. Incertain embodiments, a gastrointestinal and/or urology stent can have anexpanded diameter of from 6 mm to about 30 mm. In some embodiments, aneurology stent can have an expanded diameter of from about 1 mm toabout 12 mm. An Abdominal Aortic Aneurysm (AAA) stent and a ThoracicAortic Aneurysm (TAA) stent can have a diameter from about 20 mm toabout 46 mm.

Stent 20 can include one or more struts including the surface portion 32and the underlying portion 34. In some embodiments, the stent isentirely bioerodible. In other embodiments, the stent can include bothbioerodible and non-bioerodible portions. In some embodiments, the stent20 can include selective treatment of various bands 22 and/or connectors24 to create a stent that erodes at a faster rate in predetermined areasand in a predetermined pattern to control the overall erosion process ofthe stent. For example, a preferential erosion of connectors 24 canrelieve strain in the bands 22. The preferential erosion areas can beproduced either by having different regions with different amountsand/or types of corrosion enhancing deposits 28, by having differentregions having different surface portion thicknesses, and/or by havingsome portions that lack the corrosion enhancing deposits 28.

The stent 20 can, in some embodiments, be adapted to release one or moretherapeutic agents. The term “therapeutic agent” includes one or more“therapeutic agents” or “drugs.” The terms “therapeutic agents” and“drugs” are used interchangeably and include pharmaceutically activecompounds, nucleic acids with and without carrier vectors such aslipids, compacting agents (such as histones), viruses (such asadenovirus, adeno-associated virus, retrovirus, lentivirus and a-virus),polymers, antibiotics, hyaluronic acid, gene therapies, proteins, cells,stem cells and the like, or combinations thereof, with or withouttargeting sequences. The delivery mediated is formulated as needed tomaintain cell function and viability. A common example of a therapeuticagent includes Paclitaxel.

The stent 20 can, in some embodiments, also include one or more coatingsoverlying the surface portion 32. In some embodiments, a surface coatingcan further delay the erosion of the surface portion 32. In someembodiments, a coating can be a drug-eluting coating that includes atherapeutic agent.

Stent 20 can be used, e.g., delivered and expanded, using a catheterdelivery system. Catheter systems are described in, for example, WangU.S. Pat. No. 5,195,969, Hamlin U.S. Pat. No. 5,270,086, andRaeder-Devens, U.S. Pat. No. 6,726,712. Stents and stent delivery arealso exemplified by the Sentinol® system, available from BostonScientific Scimed, Maple Grove, Minn.

In some embodiments, stents can also be a part of a covered stent or astent-graft. In other embodiments, a stent can include and/or beattached to a biocompatible, non-porous or semi-porous polymer matrixmade of polytetrafluoroethylene (PTFE), expanded PTFE, polyethylene,urethane, or polypropylene.

In some embodiments, stents can be formed by fabricating a wire having asurface portion overlying an underlying portion, the underlying portionincluding the corrosion enhancing deposits, and knitting and/or weavingthe wire into a tubular member.

All publications, references, applications, and patents referred toherein are incorporated by reference in their entirety.

Other embodiments are within the claims.

1. An endoprosthesis comprising a tubular member defined by a pluralityof struts, at least one strut of the tubular member having a centrallongitudinal axis and including: (a) a central portion of the at leastone strut that extends along the central longitudinal axis, the centralportion lacking corrosion enhancing deposits; (b) an underlying portioncomprising a first bioerodible metal including a matrix and corrosionenhancing deposits within the matrix, the underlying portion extendingradially outward from the central portion relative to the centrallongitudinal axis; the underlying portion having a thickness of at least1 micrometer; (c) a surface portion having a thickness of between 0.1micrometers and 3micrometers overlying and extending radially outwardfrom the underlying portion relative to the central longitudinal axis,the surface portion comprising a second bioerodible metal having thecomposition of the matrix and being substantially free of corrosionenhancing deposits; the surface portion having a first erosion rate andthe underlying portion having a second erosion rate that is greater thanthe first erosion rate when the surface portion and the underlyingportion are exposed to physiological environments.
 2. The endoprosthesisof claim 1, wherein the corrosion enhancing deposits of the underlyingportion comprise nano-bubbles of noble gases.
 3. The endoprosthesis ofclaim 2, wherein the nano-bubbles comprise helium, argon, neon, krypton,or a combination thereof.
 4. The endoprosthesis of claim 2, wherein thenano-bubbles have an average diameter of between 1 nm and 600 nm.
 5. Theendoprosthesis of claim 1, wherein the corrosion enhancing deposits ofthe underlying portion comprise silver.
 6. The endoprosthesis of claim1, wherein the corrosion enhancing deposits of the underlying portioncomprise manganese.
 7. The endoprosthesis of claim 1, wherein thecorrosion enhancing deposits in the underlying portion are more noblethan the first bioerodible metal and form a galvanic couple with thefirst bioerodible metal when the corrosion enhancing deposits in theunderlying portion are exposed to physiological environments and thecorrosion enhancing deposits in the underlying portion act as an anode.8. The endoprosthesis of claim 1, wherein the corrosion enhancingdeposits in the underlying portion are less noble than the firstbioerodible metal and form a galvanic couple with the first bioerodiblemetal when the corrosion enhancing deposits in the underlying portionare exposed to physiological environments and the corrosion enhancingdeposits in the underlying portion act as an cathode.
 9. Theendoprosthesis of claim 1, wherein the surface portion consistsessentially of the second bioerodible metal.
 10. The endoprosthesis ofclaim 1, wherein the surface portion has a substantially smooth uppersurface.
 11. The endoprosthesis of claim 1, wherein the first and secondbioerodible metals comprises iron or an alloy thereof.
 12. Theendoprosthesis of claim 1, wherein the endoprosthesis is a stent. 13.The endoprosthesis of claim 1, wherein the underlying portion has athickness of between 2 and 3 micrometers.